## Hiding behind chaos and error in the double pendulum

If you want a visual intuition for just how unpredictable chaotic dynamics can be then the go-to toy model is the double pendulum. There are lots of great simulations (and some physical implementations) of the double pendulum online. Recently, /u/abraxasknister posted such a simulation on the /r/physics subreddit and quickly attracted a lot of attention.

In their simulation, /u/abraxasknister has a fixed center (block dot) that the first mass (red dot) is attached to (by an invisible rigid massless bar). The second mass (blue dot) is then attached to the first mass (also by an invisible rigid massless bar). They then release these two masses from rest at some initial height and watch what happens.

The resulting dynamics are at right.

It is certainly unpredictable and complicated. Chaotic? Most importantly, it is obviously wrong.

But because the double pendulum is a famous chaotic system, some people did not want to acknowledge that there is an obvious mistake. They wanted to hide behind chaos: they claimed that for a complex system, we cannot possibly have intuitions about how the system should behave.

In this post, I want to discuss the error of hiding behind chaos, and how the distinction between microdynamics and global properties lets us catch /u/abraxasknister’s mistake.

## Span programs as a linear-algebraic representation of functions

I feel like TheEGG has been a bit monotone in the sort of theoretical computer science that I’ve been writing about recently. In part, this has been due to time constraints and the pressure of the weekly posting schedule (it has now been over a year with a post every calendar week); and in part due to my mind being too fixated on algorithmic biology.

So for this week, I want to change things up a bit. I want to discuss some of the math behind a success of cstheory applied to nature: quantum computing. It’s been six years since I blogged about quantum query complexity and the negative adversary method for lower bounding it. And it has been close to 8 years since I’ve worked on the topic.

But I did promise to write about span programs — a technique used to reason about query complexity. So in this post, I want to shift gears to quantum computing and discuss span programs. I doubt this is useful to thinking about evolution, but it never hurts to discuss a cool linear-algebraic representation of functions.

I started writing this post for the CSTheory Community Blog. Unfortunately, that blog is largely defunct. So, after 6 years, I decided to post on TheEGG instead.

## Space-time maps & tracking colony size with OpenCV in Python

One of the things that the Department of Integrated Mathematical Oncology at the Moffitt Cancer Center is doing very well, is creating an atmosphere that combines mathematics and experiment in cancer. Fellow TheEGG blogger, Robert Vander Velde is one of the new generation of cancer researchers who are combining mathematics and experiment. Since I left Tampa, I’ve had less opportunity to keep up with the work at the IMO, but occasionally I catch up on Slack.

A couple of years ago, Robert had a computer science question. One at the data analysis and visualization stage of the relationship between computer science and cancer. Given that I haven’t posted code on TheEGG in a long time, I thought I’d share some visualizations I wrote to address Robert’s question.

There are many ways to measure the size of populations in biology. Given that we use it in our game assay, I’ve written a lot about using time-lapse microscopy of evolving populations. But this isn’t the only — or most popular — approach. It is much more common to dillute populations heavily and then count colony forming units (CFUs). I’ve discussed this briefly in the context of measuring stag-hunting bacteria.

But you can also combine both approaches. And do time-lapse microscopy of the colonies as they form.

A couple of years ago, Robert Vander Velde Andriy Marusyk were working on experiments that use colony forming units (CFUs) as a measure of populations. However, they wanted to dig deeper into the heterogeneous dynamics of CFUs by tracking the formation process through time-lapsed microscopy. Robert asked me if I could help out with a bit of the computer vision, so I wrote a Python script for them to identify and track individual colonies through time. I thought that the code might be useful to others — or me in the future — so I wanted to write a quick post explaining my approach.

This post ended up trapped in the drafts box of TheEGG for a while, but I thought now is as good a time as any to share it. I don’t know where Robert’s work on this has gone since, or if the space-time visualizations I developed were of any use. Maybe he can fill us in in the comments or with a new guest post.

## Game landscapes: from fitness scalars to fitness functions

My biology writing focuses heavily on fitness landscapes and evolutionary games. On the surface, these might seem fundamentally different from each other, with their only common feature being that they are both about evolution. But there are many ways that we can interconnect these two approaches.

The most popular connection is to view these models as two different extremes in terms of time-scale.

When we are looking at evolution on short time-scales, we are primarily interested which of a limited number of extant variants will take over the population or how they’ll co-exist. We can take the effort to model the interactions of the different types with each other, and we summarize these interactions as games.

But when we zoom out to longer and longer timescales, the importance of these short term dynamics diminish. And we start to worry about how new types arise and take over the population. At this timescale, the details of the type interactions are not as important and we can just focus on the first-order: fitness. What starts to matter is how fitness of nearby mutants compares to each other, so that we can reason about long-term evolutionary trajectories. We summarize this as fitness landscapes.

From this perspective, the fitness landscapes are the more foundational concept. Games are the details that only matter in the short term.

But this isn’t the only perspective we can take. In my recent contribution with Peter Jeavons to Russell Rockne’s 2019 Mathematical Oncology Roadmap, I wanted to sketch a different perspective. In this post I want to sketch this alternative perspective and discuss how ‘game landscapes’ generalize the traditional view of fitness landscapes. In this way, the post can be viewed as my third entry on progressively more general views of fitness landscapes. The previous two were on generalizing the NK-model, and replacing scalar fitness by a probability distribution.

In this post, I will take this exploration of fitness landscapes a little further and finally connect to games. Nothing profound will be said, but maybe it will give another look at a well-known object.

## Constant-sum games as a way from non-cell autonomous processes to constant tumour growth rate

A lot of thinking in cancer biology seems to be focused on cell-autonomous processes. This is the (overly) reductive view that key properties of cells, such as fitness, are intrinsic to the cells themselves and not a function of their interaction with other cells in the tumour. As far as starting points go, this is reasonable. But in many cases, we can start to go beyond this cell-autonomous starting point and consider non-cell-autonomous processes. This is when the key properties of a cell are not a function of just that cell but also its interaction partners. As an evolutionary game theorist, I am clearly partial to this view.

Recently, I was reading yet another preprint that has observed non-cell autonomous fitness in tumours. In this case, Johnson et al. (2019) spotted the Allee effect in the growth kinetics of cancer cells even at extremely low densities (seeding in vitro at <200 cells in a 1 mm^3 well). This is an interesting paper, and although not explicitly game-theoretic in its approach, I think it is worth reading for evolutionary game theorists.

Johnson et al.'s (2019) approach is not explicitly game-theoretic because they consider their in vitro populations as a monomorphic clonal line, and thus don't model interactions between types. Instead, they attribute non-cell autonomous processes to density dependence of the single type on itself. In this setting, they reasonably define the cell-autonomous null-model as constant exponential growth, i.e. $\dot{N}_T = w_TN_T$ for some constant fitness $w_T$ and total tumour size $N_T$.

It might also be tempting to use the same model to capture cell-autonomous growth in game-theoretic models. But this would be mistaken. For this is only effectively cell-autonomous at the level of the whole tumour, but could hide non-cell-autonomous fitness at the level of the different types that make up the tumour. This apparent cell-autonomous total growth will happen whenever the type interactions are described by constant-sum games.

Given the importance of constant-sum games (more famously known as zero-sum games) to the classical game theory literature, I thought that I would write a quick introductory post about this correspondence between non-cell autonomous constant-sum games and effectively cell-autonomous growth at the level of the whole tumour.

## Quick introduction: Evolutionary game assay in Python

It’s been a while since I’ve shared or discussed code on TheEGG. So to avoid always being too vague and theoretical, I want to use this post to explain how one would write some Python code to measure evolutionary games. This will be an annotated sketch of the game assay from our recent work on measuring evolutionary games in non-small cell lung cancer (Kaznatcheev et al., 2019).

The motivation for this post came about a month ago when Nathan Farrokhian was asking for some advice on how to repeat our game assay with a new experimental system. He has since done so (I think) by measuring the game between Gefitinib-sensitive and Gefitinib-resistant cell types. And I thought it would make a nice post in the quick introductions series.

Of course, the details of the system don’t matter. As long as you have an array of growth rates (call them yR and yG with corresponding errors yR_e and yG_e) and initial proportions of cell types (call them xR and xG) then you could repeat the assay. To see how to get to this array from more primitive measurements, see my old post on population dynamics from time-lapse microscopy. It also has Python code for your enjoyment.

In this post, I’ll go through the two final steps of the game assay. First, I’ll show how to fit and visualize fitness functions (Figure 3 in Kaznatcheev et al., 2019). Second, I’ll transform those fitness functions into game points and plot (Figure 4b in Kaznatcheev et al., 2019). I’ll save discussions of the non-linear game assay (see Appendix F in Kaznatcheev et al., 2019) for a future post.

## Local peaks and clinical resistance at negative cost

Last week, I expanded on Rob Noble’s warning about the different meanings of de novo resistance with a general discussion on the meaning of resistance in a biological vs clinical setting. In that post, I suggested that clinicians are much more comfortable than biologists with resistance without cost, or more radically: with negative cost. But I made no argument — especially no reductive argument that could potentially sway a biologist — about why we should entertain the clinician’s perspective. I want to provide a sketch for such an argument in this post.

In particular, I want to present a theoretical and extremely simple fitness landscape on which a hypothetical tumour might be evolving. The key feature of this landscape is a low local peak blocking the path to a higher local peak — a (partial) ultimate constraint on evolution. I will then consider two imaginary treatments on this landscape, one that I find to be more similar to a global chemotherapy and one that is meant to capture the essence of a targetted therapy. In the process, I will get to introduce the idea of therapy transformations to a landscape — something to address the tendency of people treating treatment fitness landscapes as completely unrelated to untreated fitness landscapes.

Of course, these hypothetical landscapes are chosen as toy models where we can have resistance emerge with a ‘negative’ cost. It is an empirical question to determine if any of this heuristic capture some important feature of real cancer landscapes.

But we won’t know until we start looking.

## Effective games from spatial structure

For the last week, I’ve been at the Institute Mittag-Leffler of the Royal Swedish Academy of Sciences for their program on mathematical biology. The institute is a series of apartments and a grand mathematical library located in the suburbs of Stockholm. And the program is a mostly unstructured atmosphere — with only about 4 hours of seminars over the whole week — aimed to bring like-minded researchers together. It has been a great opportunity to reconnect with old colleagues and meet some new ones.

During my time here, I’ve been thinking a lot about effective games and the effects of spatial structure. Discussions with Philip Gerlee were particularly helpful to reinvigorate my interest in this. As part of my reflection, I revisited the Ohtsuki-Nowak (2006) transform and wanted to use this post to share a cute observation about how space can create an effective game where there is no reductive game.

Suppose you were using our recent game assay to measure an effective game, and you got the above left graph for the fitness functions of your two types. On the x-axis, you have seeding proportion of type C and on the y-axis you have fitness. In cyan you have the measured fitness function for type C and in magenta, you have the fitness function for type D. The particular fitnesses scale of the y-axis is not super important, not even the x-intercept — I’ve chosen them purely for convenience. The only important aspect is that the cyan and magenta lines are parallel, with a positive slope, and the magenta above the cyan.

This is not a crazy result to get, compare it to the fitness functions for the Alectinib + CAF condition measured in Kaznatcheev et al. (2018) which is shown at right. There, cyan is parental and magenta is resistant. The two lines of best fit aren’t parallel, but they aren’t that far off.

How would you interpret this sort of graph? Is there a game-like interaction happening there?

Of course, this is a trick question that I give away by the title and set-up. The answer will depend on if you’re asking about effective or reductive games, and what you know about the population structure. And this is the cute observation that I want to highlight.

## Looking for species in cancer but finding strategies and players

Sometime before 6 August 2014, David Basanta and Tamir Epstein were discussing the increasing focus of mathematical oncology on tumour heterogeneity. An obstacle for this focus is a good definitions of heterogeneity. One path around this obstacle is to take definitions from other fields like ecology — maybe species diversity. But this path is not straightforward: we usually — with some notable and interesting examples — view cancer cells as primarily asexual and the species concept is for sexual organisms. Hence, the specific question that concerned David and Tamir: is there a concept of species that applies to cancer?

I want to consider a couple of candidate answers to this question. None of these answers will be a satisfactory definition for species in cancer. But I think the exercise is useful for understanding evolutionary game theory. With the first attempt to define species, we’ll end up using the game assay to operationalize strategies. With the second attempt, we’ll use the struggle for existence to define players. Both will be sketches that I will need to completely more carefully if there is interest.

## Token vs type fitness and abstraction in evolutionary biology

There are only twenty-six letters in the English alphabet, and yet there are more than twenty-six letters in this sentence. How do we make sense of this?

Ever since I first started collaborating with David Basanta and Jacob Scott back in 2012/13, a certain tension about evolutionary games has been gnawing at me. A feeling that a couple of different concepts are being swept up under the rug of a single name.[1] This feeling became stronger during my time at Moffitt, especially as I pushed for operationalizing evolutionary games. The measured games that I was imagining were simply not the same sort of thing as the games implemented in agent-based models. Finally this past November, as we were actually measuring the games that cancer plays, a way to make the tension clear finally crystallized for me: the difference between reductive and effective games could be linked to two different conceptions of fitness.

This showed a new door for me: philosophers of biology have already done extensive conceptual analysis of different versions of fitness. Unfortunately, due to various time pressures, I could only peak through the keyhole before rushing out my first draft on the two conceptions of evolutionary games. In particular, I didn’t connect directly to the philosophy literature and just named the underlying views of fitness after the names I’ve been giving to the games: reductive fitness and effective fitness.

Now, after a third of a year busy teaching and revising other work, I finally had a chance to open that door and read some of the philosophy literature. This has provided me with a better vocabulary and clearer categorization of fitness concepts. Instead of defining reductive vs effective fitness, the distinction I was looking for is between token fitness and type fitness. And in this post, I want to discuss that distinction. I will synthesize some of the existing work in a way that is relevant to separating reductive vs. effective games. In the process, I will highlight some missing points in the current debates. I suspect this points have been overlooked because most of the philosophers of biology are focused more on macroscopic organisms instead of the microscopic systems that motivated me.[2]

Say what you will of birds and ornithology, but I am finding reading philosophy of biology to be extremely useful for doing ‘actual’ biology. I hope that you will, too.